Soft tissue calcification is a major cause of morbidity and mortality in dialysis patients. This calcification of soft tissue is believed to be due to excess amounts and/or accumulation of calcium and phosphorus in the body. See G. R. Bailie, Calcium and Phosphorus management in chronic kidney disease: Challenges and trends, 39 Formulary pp. 358-365 (2004). Vascular calcification is particularly problematic in dialysis patients as it associated with myocardial dysfunction, heart failure, and cardiac arrest. Id.
Generally, plasma calcium concentrations are maintained within very narrow limits (typically between about 1.1 and about 1.3 mmol/L). See J. T. Daugirdas, P. G. Blake, and T. S. Ing, Handbook of Dialysis, (2007). Hormonally, calcium levels are regulated by parathyroid hormone (PTH), which is secreted by the parathyroid glands in response to a decrease in ionized calcium (Ca2+) below its normal range. PTH stimulates the movement of calcium and its counterion phosphorus from the bone to the blood and extracellular fluid (ECF) and further increases calcium resorption and phosphorus excretion by the kidney. Calcium levels are also controlled by intake of vitamin D3, which increases calcium and phosphorus absorption by the intestines, the primary site in regulating dietary calcium absorption. The intake of vitamin D3 can be from dietary sources or from vitamin D3 analogs, such as, for example, calcitriol (e.g, Rocaltrol®), doxercalciferol (e.g., Hectorol®), or paricalcitol (e.g., Zemplar®). Ionized calcium levels that are too low result in hyperexcitability and tetanic convulsions whereas ionized calcium levels that are too high can cause death due to muscle paralysis and coma.
Despite the importance in regulating calcium levels during hemodialysis, how to control calcium balance in dialysis patients is poorly understood. In patients having chronic renal failure, both net calcium absorption and calcium intake are generally reduced, however, as discussed above, the use of IV Vitamin D3 increases calcium absorption. In addition, the failure in the glomerular filtration rate (GFR) of the kidney leads to a decrease in urinary calcium excretion. Thus, decreased excretion causes patients with end-stage renal disease (ESRD) to typically have positive serum calcium mass balances.
Similarly, phosphorus accumulates in patients with renal insufficiency due to lack of excretion of phosphorus by the kidney and this excess phosphorus is often not sufficiently eliminated by dialysis treatments. Consequently, nearly all ESRD patients develop hyperphosphatemia. Id. An additional complication caused by elevated levels of serum phosphorus is increased calcium-phosphorus (Ca×P) product, that must be maintained below a threshold value of 55 mg2/dL2 in order to prevent precipitation of calcium phosphate and calcification of vascular, cardiac, and other soft tissues. Id. To remove excess phosphorus, however, patients are generally given phosphate binders, such as calcium acetate or calcium carbonate, and these calcium containing compounds further add to the calcium load in the patients. Still, calcium levels must be maintained within normal concentrations as low ionized calcium levels can lead to hypotension, decreased myocardial contractility, and aggravation of secondary hypoparathyroidism.
Despite the need to control a hemodialysis patient's intradialytic calcium and phosphorus mass balances to account for the patient's interdialytic calcium and phosphorus mass balances, there has heretofore not been a satisfactory method for doing so. One problem in doing so, for example, is that a patient's interdialytic calcium and phosphorus accumulation or depletion cannot be accurately determined by simply measuring the patient's serum calcium concentration before a hemodialysis treatment. This is because, for example, physiological regulation of serum calcium maintains the serum calcium concentration within a narrow range which is not indicative of the patient's interdialytic calcium mass balance.
In the past 20 years, a similar problem in assessing the adequacy of dialysis has been addressed by urea kinetic modeling (UKM). Modeling was necessary because a low concentration of urea in the blood after a dialysis treatment could be the result of either poor nutritional intake or adequate dialysis. See National Kidney Foundation Clinical Practice Guidelines for Hemodialysis Adequacy, American Journal of Kidney Diseases, Vol 30 (3) Suppl. 2 (1997). The standard measure of dialysis adequacy is called Kt/V, a dimensionless quantity composed of K, the dialyzer's rate of clearance of a substance from the patient's blood, typically measured in mL/min, the total time of the dialysis treatment, typically measured in minutes, and the volume of distribution of that substance in the patient's body, typically measured in liters (and converted to mL). A typical value of Kt/V for adequate dialysis is about 1.2, which, for a given patient (constant V) can be achieved by a dialysis treatment for a longer time (larger t), or a higher efficiency dialyzer (higher K). The substance chosen as a marker of dialysis adequacy was urea. See F. G. Casino, and T. Lopez, The equivalent renal urea clearance. A new parameter to assess dialysis dose, Nephrol. Dial. Transplant., Vol. 11 pp. 1574-1581 (1996).
Urea is the major end product of protein catabolism, making up about 90% of waste nitrogen accumulating in body water between dialysis treatments. While urea itself is not particularly toxic, its concentration is easily calculated from a blood urea nitrogen (BUN) measurement, and therefore it was adopted as an index for measuring the adequacy of dialysis. The BUN is a concentration, typically expressed in mg/dL, however, and therefore the other variable required to obtain the grams of urea is the volume of distribution of urea in the patient's body. The volume of distribution is obtained from urea kinetic modeling (UKM), which takes into account the movement of urea from poorly perfused areas (such as the arms and legs) to the extracellular space, after dialysis has been completed. This volume of distribution is termed double pool or equilibrated volume of distribution, and the end result is termed the equilibrated protein catabolic rate (ePCR). See T. Depner, and J. Daugirdas, Equations for normalized protein catabolic rate based on two-point modeling of hemodialysis urea kinetics, Journal of the American Society of Nephrology, Vol. 7 (5), pp. 780-785 (1996).
There is a need to apply the kinetic modeling approach to phosphorus management, to quantify the amount of phosphorus and calcium absorbed by the patient from their diet as well as the amount removed by dialysis treatment and phosphorus binder dosage, so that dialysis treatment parameters and medication prescriptions can be tailored to the needs of an individual patient. This approach will be termed phosphorus kinetic modeling (PKM).